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EGFR-TKI (E) therapy yielded a better PFS than standard cytotoxic chemotherapy (C) therapy and a comparable OS in untreated patients with EGFR-mt tumors, suggesting that each of the treatments is now crucial for such subpopulation. But, it has not been fully evaluated yet which of each should be initiated first, and to what degree both of two are actually administered in early line setting in the treatment course. We here investigated a potential difference in incidence and pattern of delivery of subsequent crossover therapy after failure to each of the treatments in patients with EGFR-mt tumors.Consecutive 79 patients with advanced EGFR-mt NSCLC were retrospectively assessed who underwent E therapy (n = 39) or standard C therapy (n = 40) in the 1st-line setting between 2007 and 2011.In the E group, 16 (41%) of 39 patients were still on 1st-line E therapy. Nine (39%) of the remaining 23 could not receive standard C therapy after failure to E therapy due to symptomatic CNS metastasis (mets) in six, skeletal events in two, and patient refusal in one, whilst in C group only one (3%) of 40 failed to receive subsequent E therapy because of relapse (carcinomatous lymphangitis) (chi-square test; P < 0.001). Also, at the time of relapse to the 1-st line therapy, PS deteriorated more frequently in E group (8 of 23 versus 7 of 40; P = 0.042) and, relapse with symptomatic CNS mets seemed frequently observed in E group (6 of 23 versus 4 of 40; P = 0.093). Multivariate analysis revealed the type of regimens undergone in the 1st-line setting (E versus C) correlated with failure of administration of subsequent crossover therapy (odd ratio: 3.224, 95%CI: 1.032–5.417, P = 0.004).It seems that patients with EGFR-mt tumors who were treated with 1st-line C had better opportunity to receive post-progression E therapy than those treated with 1st-line E had chance to receive subsequent C therapy, possibly due to the difference in PS deterioration rate and relapse pattern.